Functional interaction between peroxisome proliferator-activated receptor γ and β-catenin
Functional interaction between peroxisome proliferator-activated receptor γ and β-catenin
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DOI：
10.1128/mcb.00441-06
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Farmer, Stephen R.
中科院分区：
文献类型：
--
作者：
Liu, Jiajian;Wang, Hong;Farmer, Stephen R.
研究已经证明了β-连环蛋白和过氧化物酶体增殖物激活受体γ（PPAR γ）信号通路之间的串扰。具体而言，激活的过氧化物酶体受体γ诱导β-连环蛋白的蛋白酶体降解细胞表达腺瘤性息肉病大肠杆菌含有破坏复合物。相反，致癌β-连环蛋白对这种降解具有抗性，并抑制PPAR γ靶基因的表达。在目前的研究中，我们证明了β-连环蛋白和PPAR γ之间的功能相互作用，涉及T细胞因子（TCF）/淋巴细胞增强因子（LEF）结合结构域的β-连环蛋白和连环蛋白结合结构域（CBD）内的PPAR γ。致癌β-连环蛋白（S37 A）的TCF/LEF结合结构域中的K312和K435突变显著降低了其与PPAR γ相互作用并抑制其活性的能力。此外，这些突变使得S37 A β-连环蛋白响应于PPAR γ的活化而易受蛋白酶体降解的影响。PPARgamma的CBD（螺旋7和8）内的F372突变破坏其与β-连环蛋白的结合，并显著降低PPARgamma诱导β-连环蛋白的蛋白酶体降解的能力。我们认为，在正常细胞中，过氧化物酶体增殖物激活物受体γ可以发挥作用，抑制肿瘤发生和/或Wnt信号通过靶向磷酸化β-连环蛋白的蛋白酶体通过一个过程，涉及其CBD。相反，致癌β-连环蛋白通过抑制PPAR γ活性来抵抗蛋白酶体降解，这需要其TCF/LEF结合结构域。
Studies have demonstrated cross talk between beta-catenin and peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling pathways. Specifically, activation of PPAR gamma induces the proteasomal degradation of beta-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic P-catenin is resistant to such degradation and inhibits the expression of PPAR gamma target genes. In the present studies, we demonstrate a functional interaction between beta-catenin and PPAR gamma that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of P-catenin and a catenin binding domain (CBD) within PPAR gamma. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic P-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPAR gamma. Furthermore, these mutations render S37A beta-catenin susceptible to proteasomal degradation in response to activation of PPAR gamma. Mutation of F372 within the CBD (helices 7 and 8) of PPAR gamma disrupts its binding to beta-catenin and significantly reduces the ability of PPAR gamma to induce the proteasomal degradation of beta-catenin. We suggest that in normal cells, PPAR gamma can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated beta-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic beta-catenin resists proteasomal degradation by inhibiting PPAR gamma activity, which requires its TCF/LEF binding domain.